Recent clinical observations on coronary artery spasm have generated renewed interest that vasomotion might be involved in the etiology of angina pectoris and myocardial infarction. At the same time, the post-myocardial infarction thrombolytic therapy has proven to be very successful: a result which supports the view of an occlusive thrombus within the coronary artery as the cause for myocardial infarction. Rather than view coronary vasomotion and thrombus formation as two completely separate entities, this grant proposal presents the hypothesis that in the presence of a coronary artery stenosis, coronary vasomotion can critically narrow the stenosis and result in the eventual formation of an occlusive thrombus. To examine this hypothesis, a closed-chest canine model of coronary artery stenosis will be employed. A specially designed catheter will be inserted into the left anterior descending coronary artery. This catheter will be used to electrically generate a stenosis within the vessel and to measure proximal and distal coronary artery pressure. Xenon133 will be employed to measure regional myocardial blood flow and histological examination will be used to verify the presence or absence of an occlusive thrombus. The first set of experiments will show that in the presence of a severe coronary artery stenosis, vasoactive stimuli critically narrow the stenosis and result in thrombus formation. The remaining experiments will examine, in detail, the conditions under which this occurs. In particular, the second experimental group will determine if a minimal, initial stenosis is required. The third experimental group will examine the hypothesis that vasoactive stimuli are required to critically narrow a stenosis and result in an occlusive thrombus. The last experimental group will study the importance of platelet accumulation in the occlusive thrombus formation and if platelet accumulation enhances the vasoactive responses. The information gained in the study will provide new insight into the pathogenesis of angina pectoris, ventricular fibrillation, and myocardial infarction. This new knowledge will be of vital importance to the millions of Americans suffering from coronary heart disease and may help to interpret clinical data and shape future therapy.